The following is responsive to research objective #4 titled Transmissible Spongiform Encephalopathies (TSEs): The need to understand the mechanisms of pathogenesis of the transmissible spongiform encephalopathies (TSE), the causative agent of which is the prion, has acquired an increased urgency in recent years. The recent evidence from the United Kingdom that a new variant of Creutzfeldt-Jakob disease (vCJD) in humans is related to "mad cow" disease, bovine spongiform encephalopathy (BSE), and the observation of an ever-growing outbreak of chronic wasting disease among deer and elk in the United States have brought the issue of prion diseases into the spotlight. An increased understanding of the way in which prions, unusual "protein only" infectious agents, cause disease may allow us to develop ways to enhance our biological defenses against them. One of the most intriguing aspects of prion infection is that, although the infected host exhibits no specific humoral or cellular immune response against prions, the immune system seems to aid rather than prevent prion propagation. It is likely that infecting prions first come into contact with the innate immune system of the host, specifically resident dendritic cells (DC) of the tissues. This proposal is designed to study the interaction between prions and DC. Specifically, we will test the hypothesis that prions evade the immune defenses of the host by inhibiting the differentiation and maturation of DC. Native, infectious prion, PrPsc, will be used to determine the effect of exposure to prions on DC in culture. We will use a combination of FACS analysis and functioned assays for antigen presentation to elucidate the effect of prions on the differentiation, maturation and function of DC. If we can understand the effects of prions on the innate immune system, we may be able to develop methodologies that will allow an infected host to mount a protective immune response against prion infection. At the very least, we may understand how to make better molecular and cellular reagents that could be the basis for assays that recognize pathogenic forms of PrP and thus allow a rapid and reliable diagnosis of prion disease at an early stage. [unreadable] [unreadable] [unreadable]